ASXL1 Mutations Promote Myeloid Transformation through Loss of PRC2-Mediated Gene Repression

Abdel-Wahab, Omar; Adli, Mazhar; LaFave, Lindsay M.; Gao, Jie; Hricik, Todd; Shih, Alan H.; Pandey, Suveg; Patel, Jay P.; Chung, Young Rock; Koche, Richard P.; Perna, Fabiana; Zhao, Xinyang; Taylor, Jordan E.; Park, Christopher Y.; Carroll, Martin; Melnick, Ari; Nimer, Stephen D.; Jaffe, Jacob D.; Aifantis, Iannis; Bernstein, B; Levine, Ross L.

doi:10.1016/j.ccr.2012.06.032

Cited by 515 publications

(454 citation statements)

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“…Columns represent mean 6 SEM of three independent experiments. methylation at this site, result in decreased H3K27me3, whereas mutations of genes involved in its demethylation, such as iso-citrate dehydrogenase (IDH) 1/2, result in hyper methylation (3,5,10). We, therefore, plan to expand our series of AML patient samples studied with this technique, and then perform mutational analysis of the relevant genes in order to determine if the measurement of H3K27me3 by flow cytometry is able to provide a rapid screen for mutations.…”

Section: Discussionmentioning

confidence: 99%

“…Readers bind to specific histone marks and recruit protein complexes that effect changes in chromatin condensation, gene expression, or DNA methylation. Large numbers of mutations affecting all three classes of protein have been identified in recent years, and linked to cancer progression and to other disease states (2,(5)(6)(7)(8)(9)(10)(11)(12)(13). Therefore, there is considerable interest in the development of novel agents to target these mechanisms (14,15), and, as a corollary, a need for laboratory techniques able to characterize epigenetic mechanisms in heterogeneous clinical samples, and to monitor treatment effects.…”

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The study of epigenetic mechanisms based on the analysis of histone modification patterns by flow cytoametry

et al. 2013

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Epigenetic regulation of genes involved in cell growth, survival, or differentiation through histone modifications is an important determinant of cancer development and outcome. The basic science of epigenetics uses analytical tools that, although powerful, are not well suited to the analysis of heterogeneous cell populations found in human cancers, or for monitoring the effects of drugs designed to modulate epigenetic mechanisms in patients. To address this, we selected three clinically relevant histone marks (H3K27me3, H3K9ac, and H3K9me2), modulated their expression levels by in vitro treatments to generate high and low expressing control cells, and tested the relative sensitivity of candidate antibodies to detect the differences in expression levels by flow cytometry using a range of sample preparation techniques. We identified monoclonal antibodies to all three histone marks that were suitable for flow cytometry. Staining intensities were reduced with increasing formaldehyde concentration, and were not affected by ionic strength or by alcohol treatment. A protocol suitable for clinical samples was then developed, to allow combined labeling of histone marks and surface antigens while preserving light scatter signals. This was applied to normal donor blood, and to samples obtained from 25 patients with leukemia (predominantly acute myeloid leukemia). Significant cellular heterogeneity in H3K9ac and H3K27me3 staining was seen in normal peripheral blood, but the patterns were very similar between individual donors. In contrast, H3K27me3 in particular showed considerable inter-patient heterogeneity in the leukemia cell populations. Although further refinements are likely needed to fully optimize sample staining protocols, "flow epigenetics" appears to be technically feasible, and to have potential both in basic research, and in clinical application. V C 2013 International Society for Advancement of Cytometry Key terms epigenetics; histone; leukemia; flow cytometry; drug treatment WITH the rapid development and application of sequencing technologies, it is becoming evident that alterations at the genome level are unlikely to explain the heterogeneity of human cancers (1), and there is increasing recognition that epigenetic mechanisms also play a major role in cancer development and progression. The epigenetic regulation of genes is complex, and occurs at the levels of DNA, histone proteins, and RNA (2-4). DNA methylation at promoter regions can cause long term gene silencing, whereas histone modifications, predominantly affecting lysines in the N-terminal tails of the core histone proteins H3 and H4, are more dynamic and associated with relatively short term plasticity.The most frequent lysine modifications of histone proteins ("marks") involve acetylation and methylation, although phosphorylation, ubiquitylation and sumoylation can also occur at these sites. Histone acetylation, which alters the charge distribution, is typically associated with open chromatin that enables gene transcription, whereas meth...

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The study of epigenetic mechanisms based on the analysis of histone modification patterns by flow cytoametry

et al. 2013

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“…Most of these mutations generate truncated ASXL1 proteins that retain the N-terminal region required for interaction with BAP1 (32). Although ASXL1 interaction with BAP1 was initially revealed to be dispensable for leukemia development (39), it was recently shown that leukemia-associated mutations of ASXL1 lead to an aberrant enhancement of BAP1 DUB activity (47). Moreover, expression of these ASXL1 constructs in hematopoietic precursor cell line causes an overall depletion of H2Aub associated with defects in myeloid differentiation (47).…”

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The BAP1/ASXL2 Histone H2A Deubiquitinase Complex Regulates Cell Proliferation and Is Disrupted in Cancer

Daou

Hammond-Martel

Mashtalir

et al. 2015

Journal of Biological Chemistry

104

121

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Background:The relevance of ASXL2 to the function of the histone H2A deubiquitinase BAP1 remains unknown. Results: ASXL2 promotes the assembly by BAP1 of a composite ubiquitin-binding interface (CUBI) required for DUB activity and coordination of cell proliferation. Conclusion: Cancer-associated mutations of BAP1 disrupt BAP1-ASXL2 interaction and function. Significance: We provide novel insights into BAP1 tumor suppressor function.

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“…Мутации гена ASXL1 являются вторичными генетическими событиями при МПЗ, обусловливающими неблагоприятный прогноз и рефрактерность к проводимому лечению [32].…”

Section: обзор литературыunclassified

Polycythemia Vera: New Diagnostic Concept and Its Types

Am¹,

Байков²

2016

Клиническая онкогематология

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ФГБУ «Гематологический научный центр» Минздрава России, Но-вый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167 РЕФЕРАТ Актуальность и цели. Истинная полицитемия (ИП) отно-сится к группе классических Ph-негативных миелопроли-феративных заболеваний и характеризуется панмиело-зом, панцитозом, высоким риском тромбогеморрагических осложнений, низким качеством жизни из-за присутствия симптомов опухолевой пролиферации. Малые дозы ацетил-салициловой кислоты и проведение кровопусканий/эритро-цитафереза рекомендованы для пациентов с низким риском тромбогеморрагических осложнений. Циторедуктивная те-рапия (гидроксимочевина или интерферон-α) показана паци-ентам с высоким риском тромбогеморрагических осложне-ний. В настоящее время проблемам диагностики и лечения больных ИП уделяется все большее внимание. Методы. В статье представлены краткое описание данного заболевания, обзор современных методов лечения, резуль-таты наблюдения за 100 больными ИП, которые получали терапию в поликлиническом отделении ФГБУ «Гематологи-ческий научный центр» МЗ РФ. Длительность наблюдения за пациентами составила 6-262 мес. (медиана 14 мес.). Результаты. Больные были в возрасте 23-80 лет (медиана 56 лет), доля женщин составила 67 %, мужчин -33 %. У всех пациентов диагноз ИП установлен в соответствии с класси-фикацией ВОЗ 2008 г. Мутация V617F гена JAK2 выявле-на в 100 % наблюдений. Спленомегалия констатирована у 70 % пациентов. Плеторический синдром (гиперемия лица, ладоней, инъецированность склер) наблюдался у 65 % боль-ных. Пациенты предъявляли жалобы на головную боль, го-ловокружение, а 25 % из них -на кожный зуд. Все больные получали симптоматическую терапию, антиагреганты, пре-параты, улучшающие микроциркуляцию, или антигипоксан-ты. Лечение проводилось в соответствии с клиническими рекомендациями: 49 % пациентов получали гидроксимоче-вину, 14 % -интерферон (ИФН α-2b), 14 % -комбиниро-ванную терапию (гидроксимочевину и кровопускания или ИФН α-2b и кровопускания), 23 % -только кровопускания. Ответ на лечение оценивался согласно критериям Европей-ской организации по изучению и лечению лейкозов 2009 г. Во всей группе больных без учета проводимой терапии ча-стота полных ремиссий составила 48 %, частичных -41 %, эффекта не получено у 11 %. ABSTRACT Background & Aims. Polycythemia vera (PV) refers to a group of classic Ph-negative myeloproliferative neoplasms characterized by panmyelosis, pancytosis, high risk of thrombotic and hemorrhagic complications, poor quality of life due to symptoms of tumor proliferation. Low-dose acetylsalicylic acid and phlebotomy/erythrocytapheresis are recommended for patients at low risk of complications, while the cytoreductive therapy (hydroxyurea or interferon alpha) is recommended for patients at high risk of thrombotic and hemorrhagic complications. At present, much attention is paid to the problems of diagnosis and treatment PV. Methods. The article presents a brief description of the condition, a review of modern methods of treatment, results of observation over 100 PV patients who have been treated...

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ASXL1 Mutations Promote Myeloid Transformation through Loss of PRC2-Mediated Gene Repression

Cited by 515 publications

References 53 publications

The study of epigenetic mechanisms based on the analysis of histone modification patterns by flow cytoametry

The study of epigenetic mechanisms based on the analysis of histone modification patterns by flow cytoametry

The BAP1/ASXL2 Histone H2A Deubiquitinase Complex Regulates Cell Proliferation and Is Disrupted in Cancer

Polycythemia Vera: New Diagnostic Concept and Its Types

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